I Am Number Four follows the story of John Smith, a 15-year old alien from the planet Lorien, and his guardian, Henri, as they run from the Mogadorians, another race of aliens that are hunting down John and the other eight teenage Loriens, who all make up the Garde, living on Earth. The Garde consists of all Loriens who have special Legacies and powers. The teenagers are protected by a charm, which only allows them to be killed in a set order. John is Number Four. Both the Loriens and Mogadorians have a human appearance.

The book opens with the death of Number Three. Number Four is introduced, going by the name of Daniel Jones, as he leaves Florida. Four has three circular scars wrapped around his right ankle, signifying the deaths of Numbers One, Two and Three. These scars are present on all the Lorien teenagers, and with each death, another scar appears. Henri, Four’s Cêpan (guardian), tells him they are going to Paradise, Ohio. Four chooses the name John Smith as his new alias.

Tired of running, John says that he wants to begin to make a life for himself. Henri reminds him why they run, and the conversation ends. John begins to attend the local high school, where he meets Sarah Hart, a blond junior. He also meets her ex-boyfriend Mark James, who immediately begins to pick on John. John stands up to him, the first time he has ever stood up to anybody.

In his astronomy class, John’s hands begin to hurt and glow. When John is back at his house, he realizes that his first Legacy has arrived. A Legacy is a power that only certain Loriens possess, and each differs from one Lorien to the other, except for telekinesis, which all members of the Garde are capable of performing. Henri tells John that his first Legacy is Lumen, the ability to produce light from his hands and a resistance to heat and fire. When Henri begins to help the resistance spread throughout John’s body, John has a vision of his last moments on Lorien when the Mogadorians attacked, while Henri narrates.

Henri and John have a special Lorien chest that can only be opened by John and Henri together. The only way that John can open the chest without Henri is if he dies. Henri shows John a model of the galaxies, where he can see how Lorien looked before the Morgadorians destroyed it and how it looks now, desolate and barren. The chest also has a healing stone that heals all wounds inflicted on the body, but in order to heal the wound, the injured person must endure pain twice as intense as the first time and the wound must have come from the intent to hurt or kill a Lorien. The healing stone must also be used soon after the wound is inflicted. A third item in the chest is small pebble-like rocks that John and Henri put under their tongue to reduce pain. But that immediately diminishes if a Lorien uses one of their legacies.

After his first Legacy arrives, John begins to train in combat. John can eventually turn his lights on and off by will. John also makes his first real friend, Sam Goode, who believes in aliens. He also grows closer to Sarah. At a town Halloween party, John, Sarah, Sam, and Sarah’s friend, Emily, are ambushed by Mark and his football teammates. John, who is enraged by Mark’s constant bullying and the fact that he has kidnapped Sarah, finds, confronts, and defeats him. Sam sees John’s lights and begins to avoid him. Sarah and John kiss.

John confronts Sam, and Sam turns a gun on him, asking who he really is, but John convinces him that he isn’t an alien. At a Thanksgiving dinner, John is worried when Henri doesn’t turn up at the Hart's place after going in search of the publishers of Sam’s alien conspiracy magazine. John calls Sam for help, and the two go to Athens, Ohio, where they find Henri. John’s telekinesis Legacy appears, and he uses it to save both Henri and Sam. Sam is told the truth about both John and Henri after seeing John uses telekinesis, and accepts them for who they are. John’s training begins to intensify, by being set on fire and using his telekinesis.

John and Sarah continue to grow even closer. John asks Henri is it possible for humans to love Loriens. Henri says that Loriens and humans have interbred before, creating exceptionally talented children, some of which included the Greek gods. Henri warns John not to get too attached to Sarah, as Lorien love is different from human love.

At a party at Mark’s house, a fire starts, trapping Sarah on the second floor. John rushes in and saves her, revealing who and what he really is to her in the process. She confesses her love for him however, and John says he loves her, too. He tells her everything about himself. At school the next day, John fears that he will have to leave, as people had seen him jump out of the window and reported it. However, the paper has no reference to John, but a fax sent to the school saying “Are you Number Four?” causes John to flee the school in panic through a window. When he arrives home, he sees Mark, who has realized what John is. He also has an argument with Henri about why he did what he did, saying he wanted a normal life. He returns to the school to find Sarah after realizing the Mogadorians are on their way to kill him.

John finds her, but is found by a Mogadorian scout, one of several who have closed in on the school. John kills it, and while trying to flee the school is found by Henri and Mark. The four are found by a girl around John’s age, and John’s dog, Bernie Kosar. The girl says that she is Number Six. John realizes that with Six with him, the charm protecting them from being killed out of order has now broken. Six replies that the war has begun, with Henri agreeing. As the five companions find a way out of the school, John tells Mark and Sarah to go back and hide, as it isn’t their fight. They leave, and John confronts his first soldier, whom he kills.

John is wounded severely and is rescued by Henri and Sam, who realized what was happening and came to help. John discovers his third Legacy, the ability to communicate with animals, and convinces one of the Mogadorians' beasts to turn on its masters. Henri is hit by an energy blast from a soldier and dies in John’s arms. Before he passes away, he says, "Coming here, to Paradise, it wasn't by chance."

After waking up in a hotel room, John tells Sarah he has to leave. Sarah accepts this and tells him she will wait for him. John replies in a similar fashion, saying his heart will always belong to her. Afterward, Henri’s body is cremated. Sam agrees to go with John and Six as they prepare to leave in search of the other four Loriens. The novel ends with John telling Sarah he will come back to her as he leaves.